Unlike most injuries encountered in hospitals, battlefield wounds are polytraumatic in nature involving multiple mechanisms of injury to multiple anatomical sites. In most of these injuries, contamination is an expected risk and prevention of infection and sepsis is important (Kauvar, D. D. et. al. J. Burn Care Rehab., 26 (2005), 357-61). In the case of burn related injuries, of those with greater than 40% of total body surface area burned, 75% of deaths are related to infectious complications. Furthermore, drug resistant bacteria and fungi are responsible for an increasing number of burn infections (Gamelli, R. L., 13th Annual San Antinio Trauma Symposium, 2007; Schofield, C. M., et. Al., Burns, 33 (2007), 341-346). Many antibiotic drugs and other antimicrobial agents (e.g. silver based compounds, sodium hypochlorite) are currently used in a variety of anti-microbial preparations. However, the use of these compounds has been associated with microbial resistance, allergic potential, tissue toxicity and lack of effectiveness. By preventing or reducing infection, the overall wound healing response will be optimized thus achieving an efficient and beneficial outcome following acute trauma and thermal injuries experienced by today's war fighter. Serious morbidity and mortality from wound infections are not limited to the battlefield. The development of antibiotic resistant bacterial infections in hospitals is now a major health risk to the general population as well.
The ideal infection prevention product would be one that is effective against a broad spectrum of microbes, is biocompatible, does not produce resistant bacteria and has a low potential for developing sensitivity or allergy. Such an approach would utilize the advantages inherent to iodine including the fact that iodine doesn't generate resistant strains of bacteria (Lanker Klossner, B., et. al., Dermatology, 195 (1977), Suppl. 2:10-13; Hoang, et. al, J. Clin. Pathol. 29 (1976) 753-55). Iodine has continually proven its antimicrobial effectiveness since its introduction almost two centuries ago. Not only is topical iodine effective against all deleterious microbes, it does not produce resistance in bacteria nor does it produce allergies which makes it ideal for traumatic wounds requiring immediate and effective treatment. Research has shown that molecular iodine is the most effective molecular configuration of iodine (Punyani, S., et. al., J. Appl. Poly. Science 103 (2007) 3334-3340).
The most commonly used forms of iodine disinfectant are aqueous alcoholic solutions called “tinctures”. These typically contain 2-7% molecular iodine along with potassium/sodium iodide in ethanol water mixture. Iodine in this form has many disadvantages including poor stability, high chemical reactivity, odor and skin discoloration and it often irritates and injures skin and wounds. In order to eliminate the disadvantages of “tinctures” iodine has been complexed with water soluble polymeric carriers such as polyvinylpyrrolidone (PVP) and polyvinylalcohol (PVA). Complexes of this type are called iodophors (“Advances in Polymer Science” Vol 108, 1993, 91-129). An iodophor may be defined as a complex of iodine in ionic or molecular form or both with a carrier that serves to increase the solubility of iodine in water and also provides a reservoir of iodine for a controlled and sustained release over time (U.S. Pat. No. 6,565,866, Gottlund, K. L., May 20, 2003). When a polymer is used as the carrier, these complexes are referred to as polymeric iodophors. With water soluble polymer iodophors, the concentration of free iodine in water is reduced due to the formation of micellar aggregates (U.S. Pat. No. 5,071,648, Rosenblatt, S., Dec. 10, 1991). This effect minimizes some of the disadvantages of free iodine found in “tincture” type of disinfectants i.e. odor, irritation and staining of tissue to a large degree.
Although these water soluble polymeric iodophors have an advantage over “tincture” based iodine, they still release to the wound site too quickly because of their stability. Often times, this quick release characteristic provides a much higher dose of iodine than is required for the intended antimicrobial action and the iodine is used up by side reactions with body fluids thus depleting the reservoir prematurely allowing for re-colonization of the wound site. From a clinical point of view, wound dressings based on water soluble polymeric iodophors can only contain low levels of iodine and the dressings need to be changed very frequently in use.
By utilizing a water insoluble polymeric iodophor as the carrier for iodine, the concentration of free iodine in the solution can be maintained at a low level thus avoiding the issues associated with water soluble iodophors including the premature burst like release of the iodine. Many approaches to insoluble polymer iodophors have been reported. Gottlund (U.S. Pat. No. 6,565,866B2, Gottlund, K. L., May 20, 2003) reports on the effective use of various iodine impregnated nylon fiber structures as wound dressings. These materials are not very adsorbent; they release iodine in minutes; and their iodine loading capacity is low. Rosenblatt (U.S. Pat. No. 5,071,648, Rosenblatt, S., Dec. 10, 1991)) and Cercone (U.S. Pat. No. 5,928,665, Cercone, R. J., Jul. 27, 1999) describe broad spectrum anti-microbial dressing materials based on acetalized polyvinylalcohol where PVA, a known water soluble polymeric iodophor, is made insoluble by reaction with aldehydes at substitution levels approaching thirty mole percent. These materials can typically carry up to 8% iodine by weight and this is released slowly over a period of hours. However, the acetalized PVA is unstable in contact with heavily exuding wounds releasing the acetalizing agent slowly over time thus increasing the water solubility of the iodophor and accelerating the release of iodine. Insoluble polyurethane antimicrobial foams and films have been described by Shelanski (U.S. Pat. No. 3,235,446, Shelanski, M. V., Feb. 15, 1966) and LeVeen (U.S. Pat. No. 4,381,380, LeVeen, H. H., Apr. 26, 1983). These materials are stable but can only release iodine over a period of several hours. The iodine is weakly bound to the polymer carrier as a charge transfer complex (Luo, Jie, et. al. Journal of Bioactive and Compatible Polymer. (2010), 25 (2), 185-206) and this accounts for the relatively short duration release characteristics.
There is a need therefore, for an anti-microbial polymeric iodophor that is stable, highly adsorbent, can be loaded with high levels of strongly bound iodine and can release the iodine in a controlled and sustained manner over a period of several days.